Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• (C 1 -C 4 ) alkyl denotes straight-chain or branched saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
• R 1 denotes a group -CO- (CH 2 ) 4 -CH 3 , -CH (OH) - (CH 2 ) 4 -CH 3 or -COOCH 3 .
• the compounds 1- (5- (2-quinolinylmethoxy) -2-thienyl) -1-hexanone and alpha-pentyl-5- (2-quinolinylmethoxy) -2-thiophene-methanol are particularly preferred.
• the alkylation of compounds of the formula II with the halogen compounds of the formula III according to route a) can be carried out in a polar, low-boiling organic solvent, for example in acetone or butanone, in the presence of at least 1 mol of anhydrous sodium or potassium carbonate.
• the reaction is preferably carried out in boiling 2-butanone.
• a further mole of alkali metal carbonate is necessary.
• the reaction time is approx. 5-12 hours, but can also be above or below depending on the starting materials, the solvents and the temperature.
• the reaction of compounds of the formula IV with the organometallic compounds of the formula V according to route b) can be carried out under the conditions customary in Grignard reactions. It has proven useful here to submit the organometallic compounds, dissolved in ether or THF, at a temperature of from -20 to +20 ° C., preferably at about 0 ° C., and the solution of the aldehyde of the formula IV in an inert organic solvent, for example Add ether or tetrahydrofuran, preferably in THF, dropwise with cooling.
• the compounds of formula I have weakly basic properties. They can therefore also be converted into corresponding crystalline pharmaceutically acceptable acid addition salts with corresponding strong protonic acids, such as e.g. have the hydrochloride cleaned well by recrystallization.
• a suitable solvent e.g. in a lower alcohol
• add an at least equivalent amount of strong protonic acid evaporate the solvent in vacuo and recrystallize the residue, for example from methanol or ethanol, optionally with the addition of ether.
• Such pharmaceutically acceptable acid addition salts are, in addition to the salt of hydrochloric acid, that of sulfuric acid, nitric acid, phosphoric acid and addition salts with organic acids such as acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, methanesulfonic acid and the like. These acid addition salts have the same pharmacological activity as the corresponding free bases of formula I.
• the compounds of the formula III and V are known from the literature.
• the compounds of the formulas II and IV can be prepared in a manner known per se, starting from known products.
• the compounds of the formula IV can be prepared from compounds of the formula in which R 1 is a group -COO- (Ct-C4) -alkyl. For this purpose, these compounds are reduced, for example with lithium aluminum hydride in THF, with cooling to a temperature of below 10 ° C.
• the oxidation of the alcohols thus obtained to the desired aldehydes is preferably carried out with excess pyridinium chlorochromate in methylene chloride at room temperature.
• the compounds of formula II can be synthesized in particular according to the following reaction scheme and the specific information in the examples.
• the compounds of the formula and their pharmaceutically usable acid addition salts have valuable pharmacological properties. In particular, they have a specific inhibitory effect on certain enzymes, the substrate of which is arachidonic acid. These enzymes regulate the biosynthesis of prostaglandins (PG), thromboxane A 2 (TX A 2 ) and leukotrienes (LT) in enzyme cascades.
• PG prostaglandins
• TX A 2 thromboxane A 2
• LT leukotrienes
• the 5-lipoxygenase which converts the arachidonic acid into 5-hydroperoxyeikosatetraenoic acid - a precursor of the leukotrienes - is specifically inhibited by the compounds of the formula I.
• the compounds of the formula I in which R 1 denotes the radical -CO-lower alkyl also inhibit cyclooxygenase, an enzyme which converts the arachidonic acid into prostaglandin G 2 - a precursor for other prostaglandins and TXA 2 .
• the compounds of the formula I and their pharmaceutically acceptable addition salts can be used in human medicine for diseases which are caused by a disorder of the prostaglandin, thromboxane A 2 or leukotriene metabolism.
• diseases are, for example, rheumatic arthritis, allergic diseases and asthma.
• the lipid fraction was separated by HPLC, whereby LTB 4 and its 20-OH and 20-COOH metabolites were determined photometrically at 280 nm.
• IC 50 50% inhibition
• the compounds of general formula 1 and their salts can be used as medicaments, e.g. find use in the form of pharmaceutical preparations which the compounds according to the invention in a mixture with a pharmaceutical, organic or inorganic carrier material suitable for enteral or parenteral application, for example water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols , Petroleum jelly or the like.
• a pharmaceutical, organic or inorganic carrier material suitable for enteral or parenteral application for example water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols , Petroleum jelly or the like.
• the pharmaceutical preparations can be in solid form e.g. as tablets, coated tablets, suppositories, capsules, or in liquid form e.g. present as solutions, suspensions or emulsions.
• auxiliaries such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers. They can also be administered in combination with other therapeutically valuable substances.
• the solvent is distilled off in vacuo and the residue is partitioned between ether and saturated sodium bicarbonate solution.
• the aqueous phase is extracted three times with 200 ml ether.
• the combined organic phases are washed once with water, dried over sodium sulfate / activated carbon, filtered and evaporated.
• the starting material can be produced as follows:
• the starting material can be produced as follows:
• the starting material can be produced as follows:

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Pulmonology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Pyridine Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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• 1986
  • 1986-12-23 CA CA000526227A patent/CA1297109C/en not_active Expired - Fee Related
  • 1986-12-24 US US06/947,418 patent/US4778803A/en not_active Expired - Fee Related
• 1987
  • 1987-01-07 FI FI870045A patent/FI86063C/fi not_active IP Right Cessation
  • 1987-01-12 YU YU3487A patent/YU45815B/sh unknown
  • 1987-01-13 DE DE8787100347T patent/DE3765124D1/de not_active Expired - Fee Related
  • 1987-01-13 AT AT87100347T patent/ATE56971T1/de not_active IP Right Cessation
  • 1987-01-13 EP EP87100347A patent/EP0229660B1/de not_active Expired - Lifetime
  • 1987-01-13 ES ES198787100347T patent/ES2031833T3/es not_active Expired - Lifetime
  • 1987-01-15 DD DD87299272A patent/DD259865A1/de unknown
  • 1987-01-15 NO NO870162A patent/NO165677C/no unknown
  • 1987-01-15 CS CS87280A patent/CS264287B2/cs unknown
  • 1987-01-16 KR KR1019870000296A patent/KR950009826B1/ko not_active IP Right Cessation
  • 1987-01-16 JP JP62006291A patent/JPH0784465B2/ja not_active Expired - Lifetime
  • 1987-01-16 DK DK021787A patent/DK21787A/da not_active Application Discontinuation
  • 1987-01-16 HU HU87133A patent/HU200604B/hu not_active IP Right Cessation
  • 1987-01-16 ZA ZA87311A patent/ZA87311B/xx unknown
  • 1987-01-16 AU AU67638/87A patent/AU588960B2/en not_active Ceased
  • 1987-06-12 NZ NZ218892A patent/NZ218892A/xx unknown
  • 1987-10-17 CS CS877505A patent/CS264298B2/cs unknown
  • 1987-12-22 YU YU2356/87A patent/YU45479B/xx unknown
• 1990
  • 1990-10-30 GR GR90400478T patent/GR3002512T3/el unknown
• 1992
  • 1992-04-11 SG SG399/92A patent/SG39992G/en unknown

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